This project will attempt to elucidate the role played by oxidative stress in age-related decrements in brain function of mice, as reflected by their performance in various behavioral tasks. The specific hypothesis to be tested in this proposal is that severity of the age-associated attenuations in specific cognitive and motor functions is directly related to the level of oxidative stress in specific systems of the brain. In an initial series of studies (Aim 1), immunohistochemical and biochemical techniques will be applied to identify the regions, cell populations and subcellular fractions of the brain that undergo age-associated oxidative stress. The brain sites identified in these experiments will represent the sites wherein oxidative stress may be a cause of brain dysfunction, and will provide regional focus for subsequent studies of oxidative stress, oxidative stress-activated signaling pathways (Projects 2 and 4) and calcium homeostasis (Project 3). Focusing on the sites identified in Aim 1, a second series of studies (Aim 2) will directly test for quantitative relationships between age-related behavioral impairment and oxidative stress/damage, using mice pre-screened for differences in age-related impairments of cognitive or psychomotor function. Focusing on sites identified under Aim 2, a third series of studies (Aim 3) will attempt to isolate the causes of the "impairment-associated oxidative stress" by comparing redox potential, oxidant production and antioxidant defenses in mice screened for different levels of behavioral impairment. Focusing on the targets identified in specific aims 2 and 3, a fourth study (Aim 4) will further test the oxidative stress hypothesis, by examining the degree of temporal correspondence between age-related behavioral impairments and age-related increases in oxidative stress. A fifth series of experiments (Aim 5), focusing on information obtained under Aims 2-4, will determine if experimental interventions that lower the level of oxidative stress (hormonal therapy, restriction of caloric intake or antioxidant therapy) produce concurrent delays in cognitive/psychomotor impairment and impairment-associated oxidative stress. Overall, the results of these studies should refute or validate the idea that oxidative stress is a contributory factor in age-associated decrements in cognitive or psychomotor performance.